Pancreatic cancer is the fourth leading cause of cancer death in the U.S., with a 5-year survival rate of only 4-5%. Although significant progress has been made in the past several decades to reduce the overall mortality rate of cancer, an effective treatment for pancreatic cancer remains elusive. Only ~10% of pancreatic cancer patients are suitable for surgical resection, and the remainder is offered palliative treatment to simply extend or improve their quality of life. Approximately 85% of all pancreatic cancer patients suffer from cachexia, a devastating symptom symbolized by the loss of appetite, weight, and quality of life. The standard of care of advanced pancreatic cancer patients has been the single agent chemotherapy with gemcitabine (i.e., Gemzar(R)), which offers a survival advantage of 2-3 months compared to no treatment, and only < 25% of pancreatic cancer patients are responders to it. Our long-term goal is to improve the clinical outcomes of pancreatic cancer therapy. The current proposal combines the expertise of a pharmaceutical scientist experienced in cancer experimental therapy, a cancer biologist with expertise in pancreatic cancer biology and models, and a nutritional scientist with expertise in the chemistry and biology of omega-3 polyunsaturated fatty acids (PUFAs). Data from many clinical trials showed that fish oil rich in omega-3 PUFAs is beneficial in alleviating pancreatic cancer-related cachexia. However, there is no clear clinical evidence supporting the antitumor activity omega-3 PUFAs against pancreatic ductal adenocarcinoma. Our recent promising preliminary data demonstrated that a unique integration of omega-3 PUFAs into gemcitabine therapy significantly improves the antitumor activity of gemcitabine in mouse models of pancreatic cancer. The overall objective of the present application is to comprehensively test the safety and efficacy of this unique integration in mouse models. The primary innovative aspect of this application is the novel method of utilizing omega-3 fatty acids in improving the efficacy of gemcitabine in pancreatic cancer therapy. The proposed research is significant because it addresses the urgent need to improve the overall survival and the quality of life of pancreatic cancer patients (e.g., alleviation of cachexia). Study findings will provide the initial underpinnings for future translation of this innovation into clinical trials, with the ultimate goal of establishing a highl effective approach to pancreatic cancer chemotherapy.